During iontophoresis, charged compounds pass from a reservoir attached to the skin of a person or animal into the tissue therebeneath. The process is one wherein the rate of delivery is a function of current, active agent concentration, and presence of other ions. It is a generally held belief that higher concentration of compound, higher levels of current, and lower concentration of other ions will result in greater delivery of the compound.
L. Brown and R. Langer, Ann. Rev. Med. 39:221 (1988) describe the generally held belief that the rate limiting barrier for transdermal drug delivery is the stratum corneum. There continues to be a large research effort to find methods to reduce or eliminate the rate limiting property of the stratum corneum.
N.H. Bellantone et al., International Journal of Pharmaceutics 30:63 (1986) describes how iontophoresis can be used in place of other means to enhance drug transport through the epidermal barrier such that the need for chemical penetration enhancers could be obviated. Alternatively, the article suggests use of penetration enhancers could lower drug concentrations or lower energy required for delivery.
Another technique believed to enhance the delivery of certain types of active agents by iontophoresis is disclosed in European patent application 0 278 473 A1. The application describes the addition of compounds to proteins and other macromolecules to decrease the degree of aggregation of the molecules in the active reservoir. The added compounds have the ability to aid solubility and disassociation of the macromolecules.
It is also well-known in the iontophoresis art (for example, see "Iontophoretic Delivery of Nonpeptide Drugs Formulation Optimum for Maximum Skin Permeability" by J. E. Sanderson et al, J. Pharm Sci. 78:361 (1989) that the presence of ions other than the desired compound in the donor reservoir formulation reduces iontophoretic efficiency.
In the situation of transdermal delivery where the rate limiting barrier is the stratum corneum, the dermal vasculature, which acts as the means of compound removal from the dermal tissue, has no effect on the delivery rate. Regardless of its state of dilation, it is capable of removing all the compound that reaches it. Otherwise, the vasculature would become the rate limiting barrier.
If the stratum corneum is the rate limiting barrier, placing a vasodilator near the dermal vasculature for the purpose of enhancing the blood flow through the dermal vasculature by any means, would have no effect. The rate of delivery would still be limited by the stratum corneum.
Vasodilators such as tolazoline, nitrates, papaverine, phentolamine, dipyridamole, cyclandelate, isoxsuprine, mecholyl (metacholine), histamine and nylidrin are known to dilate blood vessels. Their use with iontophoresis, without other agents, has been studied. Studies include, for example, D.I. Abramson et al., American Heart Journal, 23:817 (1942) which describes a significant increase in blood flow when using vasodilators alone.
Iontophoresis of vasodilators as a means of enhancing delivery of an active agent delivered with it has not been demonstrated. Despite attempts to optimize iontophoretic delivery by such means as varying compound concentrations and optimizing ionic moieties in the system, the efficiency of iontophoretic delivery is still low.